Abstract
To date, a number of antihypertensive peptides (AHPs) have been identified. Most of these are derived from proteins present in common edible consumables, including milk, egg, and plant foods. Consumption of these foods serves as means of AHP delivery and thus contributing favorable health benefits. It is hypothesized that food crops, either over-expressing AHP precursor proteins or producing particular peptides as heterologous components, may serve as viable vehicles for production and delivery of functional foods as alternative hypertension therapies. In recent years, genetic engineering efforts have been undertaken to add value to functional foods. Pioneering approaches have been pursued in several crop plants, such as rice and soybean. In this review, a summary of current tools used for discovery of new AHPs, as well as strategies and perspectives of capitalizing on these AHPs in genetic engineering efforts will be presented and discussed. The implications of these efforts on the development of functional foods for preventing and treating hypertension are also presented.
Similar content being viewed by others
References
Abubakar A, Saito T, Kitazawa H, Kawai Y, Itoh T (1998) Structural analysis of new antihypertensive peptides derived from cheese whey protein by proteinase K digestion. J Dairy Sci 81:3131–3138
Chen ZY, Peng C, Jiao R, Wong YM, Yang N, Huang Y (2009) Anti-hypertensive nutraceuticals and functional foods. J Agric Food Chem 57:4485–4499
Chockalingam A, Campbell NR, Fodor JG (2006) Worldwide epidemic of hypertension. Can J Cardiol 22:553–555
Cushman DW, Ondetti MA (1980) Inhibitors of angiotensin-converting enzyme for treatment of hypertension. Biochem Pharmacol 29:1871–1877
De Gasparo M, Catt KJ, Inagami T, Wright JW, Unger TH (2000) International union of pharmacology. XXIII. The angiotensin receptors. Pharmacol Rev 52:415–472
De Leo F, Panarese S, Gallerani R, Ceci LR (2009) Angiotensin Converting Enzyme (ACE) inhibitory peptides: production and implementation of functional food. Curr Phar Des 15:3622–3643
Domon B, Aebersold R (2006) Mass spectrometry and protein analysis. Science 312:212–217
Dziuba J, Minkiewicz P, Nalecz D, Iwaniak A (1999) Database of biologically active peptide sequences. Nahrung 43:190–195
Erdmann K, Cheung BW, Schröder H (2008) The possible roles of food-derived bioactive peptides in reducing the risk of cardiovascular disease. J Nutr Biochem 19:643–654
Erdos EG, Skidgel RA (1997) Metabolism of bradykinin by peptidases in health and disease. In: Farmer SG (ed) The kinin system: handbook of immunopharmacology. Academic Press, London, pp 112–141
Fida HM, Kumada Y, Terashima M, Katsuda T, Katoh S (2009) Tandem multimer expression of angiotensin I-converting enzyme inhibitory peptide in Escherichia coli. Biotechnol J 4:1345–1356
FitzGerald RJ, Meisel H (2000) Milk protein-derived peptide inhibitors of angiotensin-I-converting enzyme. Br J Nutr 84:S33–S37
FitzGerald RJ, Murray BA, Walsh DJ (2004) Hypotensive peptides from milk proteins. J Nutr 134:980S–988S
Fujita H, Yoshikawa M (1999) LKPNM: a prodrug-type ACE-inhibitory peptide derived from fish protein. Immunopharmacology 44:123–127
Fujita H, Usui H, Kurahashi K, Yoshikawa M (1995) Isolation and characterization of ovokinin, a bradykinin B1 agonist peptide derived from ovalbumin. Peptides 16:785–790
Fujita H, Yokoyama K, Yoshikawa M (2000) Classification and antihypertensive activity of angiotensin I-converting enzyme inhibitory peptides derived from food proteins. J Food Sci 65:564–569
Gobbetti M, Smacchi E, Corsetti A, Bellucci M (1997) Inhibition of proteolytic enzymes from Pseudomonas fluorescens ATCC 948 and angiotensin I-converting enzyme by peptides from zein, hordein and gluten hydrolysates. J Food Protect 60:499–504
Goossens A, Van Montagu M, Angenon G (1999) Co-introduction of an antisense gene for an endogenous seed storage protein can increase expression of a transgene in Arabidopsis thaliana seeds. FEBS Lett 456:160–164
Guang C, Phillips RD (2009) Plant food-derived Angiotensin I converting enzyme inhibitory peptides. J Agric Food Chem 57:5113–5120
Gupta N, Bark SJ, Lu WD, Taupenot L, O’Connor DT, Pevzner P, Hook V (2010) Mass spectrometry-based neuropeptidomics of secretory vesicles from human adrenal medullary pheochromocytoma reveals novel peptide products of prohormone processing. J Proteome Res 9:5065–5075
Hamamoto H, Sugiyama Y, Nakagawa N, Hashida E, Matsunaga Y, Takemoto S, Watanabe Y, Okada Y (1993) A new tobacco mosaic virus vector and its use for the systemic production of angiotensin-I-converting enzyme inhibitor in transgenic tobacco and tomato. Biotechnology (NY) 11:930–932
Hansch C, Leo A (1995) Exploring QSAR fundamentals and applications in chemistry and biology. American Chemical Society, Washington
Hata Y, Yamamoto M, Ohni M, Nakajima K, Nakamura Y, Takano T (1996) A placebo-controlled study of the effect of sour milk on blood pressure in hypertensive subjects. Am J Clin Nutr 64:767–771
Israili ZH, Hernández-Hernández R, Velasco M (2007) The future of antihypertensive treatment. Am J Ther 14:121–134
Jauhiainen T, Vapaatalo H, Poussa T, Kyronpalo S, Rasmussen M, Korpela R (2005) Lactobacillus helveticus fermented milk lowers blood pressure in hypertensive subjects in 24-h ambulatory blood pressure measurement. Am J Hypertens 18:1600–1605
Jeong DW, Shin DS, Ahn CW, Song IS, Lee HJ (2007) Expression of antihypertensive peptide, His–His-Leu, as tandem repeats in Escherichia coli. J Microbiol Biotechnol 17:952–959
Kanauchi O, Igarashi K, Ogata R, Mitsuyama K, Andoh A (2005) A yeast extract high in bioactive peptides has a blood-pressure lowering effect in hypertensive model. Curr Med Chem 12:3085–3090
Karaki H, Doi K, Sugano S, Uchiwa H, Sugai R, Murakami U, Takemoto S (1990) Antihypertensive effect of tryptic hydrolysate of milk casein in spontaneously hypertensive rats. Comp Biochem Physiol C 96:367–371
Kawasaki T, Seki E, Osajima K, Yoshida M, Asada K, Matsui T, Osajima Y (2000) Antihypertensive effect of valyl tyrosine, a short chain peptide derived from sardine muscle hydrolyzate, on mild hypertensive subjects. J Hum Hypertens 14:519–523
Kitts DD, Weiler K (2003) Bioactive proteins and peptides from food sources. Applications of bioprocesses used in isolation and recovery. Curr Pharm Des 9:1309–1323
Kodera T, Nio N (2006) Identification of an Angiotensin I-converting enzyme inhibitory peptides from protein hydrolysates by a soybean protease and the antihypertensive effects of hydrolysates in spontaneously hypertensive model rats. J Food Sci 71:C164–C173
Lau OS, Sun SS (2009) Plant seeds as bioreactors for recombinant protein production. Biotechnol Adv 27:1015–1022
Lehrer SB, Bannon GA (2005) Risks of allergic reactions to biotech proteins in foods: perception and reality. Allergy 60:559–564
Luna-Suárez S, Medina-Godoy S, Cruz-Hernández A, Paredes-López O (2010) Modification of the amaranth 11S globulin storage protein to produce an inhibitory peptide of the angiotensin I converting enzyme, and its expression in Escherichia coli. J Biotechnol 148:240–247
Maeno M, Yamamoto N, Takano T (1996) Identification of an antihypertensive peptide from casein hydrolysate produced by a proteinase from Lactobacillus helveticus CP790. J Dairy Sci 79:1316–1321
Maes W, Van Camp J, Vermeirssen V, Hemeryck M, Ketelslegers JM, Schrezenmeir J, Van Oostveldt P, Huyghebaert A (2004) Influence of the lactokinin Ala-Leu-Pro-Met-His-Ile-Arg (ALPMHIR) on the release of endothelin-1 by endothelial cells. Regul Pept 118:105–109
Majumder K, Wu J (2010) A new approach for identification of novel antihypertensive peptides from egg proteins by QSAR and bioinformatics. Food Res Intl 43:1371–1378
Masuda O, Nakamura Y, Takano T (1996) Antihypertensive peptides are present in aorta after oral administration of sour milk containing these peptides to spontaneously hypertensive rats. J Nutr 126:3063–3068
Matoba N, Doyama N, Yamada Y, Maruyama N, Utsumi S, Yoshikawa M (2001) Design and production of genetically modified soybean protein with anti-hypertensive activity by incorporating potent analogue of ovokinin(2–7). FEBS Lett 18:50–54
Matsufuji H, Matsui T, Ohshige S, Kawasaki T, Osajima K, Osajima Y (1995) Antihypertensive effects of angiotensin fragments in SHR. Biosci Biotechnol Biochem 59:1398–1401
Matsui T, Li CH, Osajima Y (1999) Preparation and characterization of novel bioactive peptides responsible for angiotensin I-converting enzyme inhibition from wheat germ. J Pept Sci 5:289–297
Megias C, Del Mar Yust M, Pedroche J, Lquari H, Giron-Calle J, Alaiz M, Millan F, Vioque J (2004) Purification of an ACE inhibitory peptide after hydrolysis of sunflower (Helianthus annuus L.) protein isolates. J Agric Food Chem 52:1928–1932
Miguel M, López-Fandiño R, Ramos M, Aleixandre A (2005) Short-term effect of egg-white hydrolysate products on the arterial blood pressure of hypertensive rats. Brit J Nutr 94:731–737
Miyoshi S, Kaneko T, Ishikawa H, Tanaka H, Maruyama S (1995) Production of bioactive peptides from corn endosperm proteins by some proteases. Ann N Y Acad Sci 750:429431
Möller NP, Scholz-Ahrens KE, Roos N, Schrezenmeir J (2008) Bioactive peptides and proteins from foods: indication for health effects. Eur J Nutr 47:171–182
Motoi H, Kodama T (2004) Isolation and characterization of angiotensin I converting enzyme inhibitory peptides from wheat gliadin hydrolysate. Nahrung 47:354–358
Mullally MM, Meisel H, FitzGerald RJ (1997) Identification of a novel angiotensin-I-converting enzyme inhibitory peptide corresponding to a tryptic fragment of bovine beta-lactoglobulin. FEBS Lett 402:99–101
Müntz K (1998) Deposition of storage proteins. Plant Mol Biol 38:77–99
Murakami M, Tonouchi H, Takahashi R, Kitazawa H, Kawai Y, Negishi H, Saito T (2004) Structural analysis of a new anti-hypertensive peptide (beta-lactosin B) isolated from a commercial whey product. J Dairy Sci 87:1967–1974
Nakamura Y, Yamamoto N, Sakai K, Takano T (1995) Antihypertensive effect of sour milk and peptides isolated from it that are inhibitors to angiotensin I-converting enzyme. J Dairy Sci 78:1253–1257
Nakashita H, Arai Y, Shikanai T, Doi Y, Yamaguchi I (2001) Introduction of bacterial metabolism into higher plants by polycistronic transgene expression. Biosci Biotechnol Biochem 65:1688–1691
Nakashima Y, Arihara K, Sasaki A, Mio H, Ishikawa S, Itoh M (2002) Antihypertensive activities of peptides derived from porcine skeletal muscle myosin in spontaneously hypertensive rats. J Food Sci 67:434–437
Nishizawa K, Kita A, Doi C, Yamada Y, Ohinata K, Yoshikawa M, Ishimoto M (2008) Accumulation of the bioactive peptides, novokinin, LPYPR and rubiscolin, in seeds of genetically modified soybean. Biosci Biotechnol Biochem 72:3301–3305
Okamoto K, Aoki K (1963) Development of a strain of spontaneously hypertensive rats. Jpn Circ J 27:282–293
Okitsu M, Morita A, Kakitani M, Okada M, Yokogoshi H (1995) Inhibition of the endothelin-converting enzyme by pepsin digests of food proteins. Biosci Biotechnol Biochem 59:325–326
Oshima G, Shimabukuro H, Nagasawa K (1979) Peptide inhibitors of angiotensin I-converting enzyme in digests of gelatin by bacterial collagenase. Biochim Biophys Acta 566:128–137
Park CJ, Lee JH, Hong SS, Lee HS, Kim SC (1998) High-level expression of the angiotensin-converting-enzyme-inhibiting peptide, YG-1, as tandem multimers in Escherichia coli. Appl Microbiol Biotechnol 50:71–76
Peach MJ (1977) Renin-angiotensin system: biochemistry and mechanisms of action. Physiol Rev 57:313–370
Pihlanto-Leppälä A, Koskinen P, Piilola K, Tupasela T, Korhonen H (2000) Angiotensin I-converting enzyme inhibitory properties of whey protein digests: concentration and characterization of active peptides. J Dairy Res 67:53–64
Pripp AH, Isaksson T, Stepaniak L, Sørhaug T (2004) Quantitative structure-activity relationship modelling of ACE nhibitory peptides derived from milk proteins. Eur Food Res Technol 219:579–583
Pripp AH, Isaksson T, Stepaniak L, Sørhaug T, Ardo Y (2005) Quantitative structure activity relationship modelling of peptides and proteins as a tool in food science. Trends Food Sci Technol 16:484–494
Quesada-Vargas T, Ruiz ON, Daniell H (2005) Characterization of heterologous multigene operons in transgenic chloroplasts: transcription, processing, and translation. Plant Physiol 138:1746–1762
Saito T (2008) Antihypertensive peptides derived from bovine casein and whey proteins. Adv Exp Med Biol 606:295–317
Sasaki K, Takahashi N, Satoh M, Yamasaki M, Minamino N (2010) A peptidomics strategy for discovering endogenous bioactive peptides. J Proteome Res 9:5047–5052
Seppo L, Jauhiainen T, Poussa T, Korpela R (2003) A fermented milk high in bioactive peptides has a blood pressure-lowering effect in hypertensive subjects. Am J Clin Nutr 77:326–330
Stoger E, Ma JK, Fischer R, Christou P (2005) Sowing the seeds of success: pharmaceutical proteins from plants. Curr Opin Biotechnol 16:167–173
Suetsuna K (1998) Isolation and characterization of angiotensin I converting enzyme inhibitor dipeptides derived from Allium sativum L (garlic). J Nutr Biochem 9:415–419
Tada Y, Utsumi S, Takaiwa F (2003) Foreign gene products can be enhanced by introduction into low storage protein mutants. Plant Biotechnol J 1:411–422
Tinoco AD, Saghatelian A (2011) Investigating endogenous peptides and peptidases using peptidomics. Biochemistry 50:7447–7461
Vercruysse L, Van Camp J, Smagghe G (2005) ACE inhibitory peptides derived from enzymatic hydrolysates of animal muscle protein: a review. J Agric Food Chem 53:8106–8115
Wakasa Y, Zhao H, Hirose S, Yamauchi D, Yamada Y, Yang L, Ohinata K, Yoshikawa M, Takaiwa F (2011) Antihypertensive activity of transgenic rice seed containing an 18-repeat novokinin peptide localized in the nucleolus of endosperm cells. Plant Biotechnol J 9:729–735
World Health Organization (2004) Regional consultation on hypertension prevention and control
World Health Organization Regional Office for the Eastern Mediterranean (2006) Guidelines for the management of hypertension in patients with diabetes mellitus
Wu J, Aluko RE, Nakai S (2006) Structural requirements of Angiotensin I-converting enzyme inhibitory peptides: quantitative structure activity relationship study of di- and tripeptides. J Agric Food Chem 54:732–738
Yamada Y, Matoba N, Usui H, Onishi K, Yoshikawa M (2002) Design of a highly potent anti-hypertensive peptide based on ovokinin(2–7). Biosci Biotechnol Biochem 66:1213–1217
Yamamoto N (1997) Antihypertensive peptides derived from food proteins. Inc Biopoly 43:129–134
Yamamoto N, Akino A, Takano T (1994) Antihypertensive effect of the peptides derived from casein by an extracellular proteinase from Lactobacillus helveticus CP790. J Dairy Sci 77:917–922
Yamada Y, Nishizawa K, Yokoo M, Zhao H, Onishi K, Teraishi M, Utsumi S, Ishimoto M, Yoshikawa M (2008) Anti-hypertensive activity of genetically modified soybean seeds accumulating novokinin. Peptides 29:331–337
Yang L, Tada Y, Yamamoto MP, Zhao H, Yoshikawa M, Takaiwa F (2006) A transgenic rice seed accumulating an anti-hypertensive peptide reduces the blood pressure of spontaneously hypertensive rats. FEBS Lett 580:3315–3320
Yang LJ, Wakasa Y, Takaiwa F (2008) Biopharming to increase bioactive peptides in rice seed. J AOAC Int 91:957–964
Yano S, Suzuki K, Funatsu G (1996) Isolation from alpha-zein of thermolysin peptides with angiotensin I-converting enzyme inhibitory activity. Biosci Biotechnol Biochem 60:661–663
Yoshikawa M, Fujita H, Matoba N, Takenaka Y, Yamamoto T, Yamauchi R, Tsuruki H, Takahata K (2000) Bioactive peptides derived from food proteins preventing lifestyle-related diseases. BioFactors 12:143–146
Zhang L, Hao GF, Tan Y, Xi Z, Huang MZ, Yang GF (2009) Bioactive conformation analysis of cyclic imides as protoporphyrinogen oxidase inhibitor by combining DFT calculations, QSAR and molecular dynamic simulations. Bioorg Med Chem 17:4935–4942
Acknowledgments
Current investigations from the group are supported by CONACYT/México (grants CB-102109, 131777, CIBIOGEM-173858) and PROMEP/SEP/México (grant CA 213 Bioprocesos).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Rosales-Mendoza, S., Paz-Maldonado, L.M.T., Govea-Alonso, D.O. et al. Engineering production of antihypertensive peptides in plants. Plant Cell Tiss Organ Cult 112, 159–169 (2013). https://doi.org/10.1007/s11240-012-0231-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11240-012-0231-9